Molecular mechanisms for direct sensing of virus-like antigens by B cells.

Particulate antigens (Ags) such as viruses can often induce strong B-cell responses in vivo very effectively, but the molecular determinants of this complex process remain incompletely understood. In this review, we focus on recent mechanistic insights into the earliest steps in the initiation of primary B-cell responses to viruses, gained by exploiting a new generation of model particulate Ag, synthetic virus-like structures. We also review the characteristics of the resulting short- and long-term antibody (Ab) responses in mice. These studies reveal that a repeating pattern of epitope display on a virus-sized scaffold is a fundamental biophysical feature of viruses that triggers a qualitatively distinct mode of B-cell Ag receptor (BCR) signal transduction relative to soluble Ag display, and consequently serves as a standalone danger signal for Ag-specific B-cell activation. Quantitative variation in epitope density (ED) on such scaffolds modulates the degree and quality of B-cell activation both in vitro and in vivo. The presence of internal nucleic acid (iNA) in the interior of these virus-like structures can profoundly influence the resulting Ab responses for the lifespan of immunized animals. We conclude that the ED of viral surface Ags and the iNA genomes provide two essential signals that together are sufficient for B-cell activation and Ab production during antiviral responses. We place these findings in the context of the literature, discuss implications for rational vaccine design, and highlight unanswered questions to guide future research directions.